Ovarian carcinoma is the deadliest gynecologic malignancy and one of the leading causes of cancer deaths for females. Because ovarian cancer is often diagnosed only after the disease has reached an advanced stage, the majority of patients require additional treatment after surgical removal of the tumor and many of those patients still die from the disease. Although greater than 70% of patients with advanced ovarian cancer respond to primary chemotherapy, most ultimately develop resistance, leading to an overall 5-year survival below 20%. For this reason novel approaches are being sought to overcome chemoresistance and to develop more effective therapies.
Currently, biological therapies are being considered as the next approach in the fight against ovarian cancer. These therapies have the potential to selectively target tumors, to minimize toxicity, and to overcome the resistance often observed with conventional therapies. One such therapy involves activating the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-pathway, that selectively induces apoptosis in tumor cells while sparing normal cells. Specifically, TRAIL triggers apoptosis rapidly through the extrinsic apoptotic pathway mediated by the death receptors, DR4 and DR5, on the cell membrane. Upon TRAIL ligand-mediated activation of the death receptor, its intracellular death domain attracts the Fas-associated death domain (FADD) adaptor molecule, which further recruits the initiator caspases 8 and 10 to the death receptor to form the death-inducing signal complex (DISC). This process ultimately results in the activation of the terminal executioner caspases 3, 6, and 7, thereby leading to cell death. Importantly, cell culture and mouse xenograft experiments have demonstrated that TRAIL can exert selective cytotoxic activity against ovarian carcinoma cells with limited effects to normal cells.
TRAIL has been implicated in several aspects of tumorigenesis including innate immune-surveillance against tumors, inhibition of tumor initiation and metastases, and in the response to conventional chemotherapy. For example, TRAIL-deficient mice show increased tumor susceptibility in response to the chemical carcinogen methylchloanthrene, and increased experimental and spontaneous metastasis. In addition, mutations in TRAIL receptors have been linked to metastatic breast cancer. Thus, activating the TRAIL pathway clinically could induce cell death and prevent metastatic disease, and those tumors that devise mechanisms to escape TRAIL-mediated apoptosis might be more metastatic.
These observations provide the basis for development of TRAIL pathway agonists (TRAIL and TRAIL receptor agonistic antibodies) for clinical trials currently in progress. However, such trials are impeded by our lack of knowledge regarding the underlying basis of tumor susceptibility to TRAIL pathway-induced death. Accordingly, there is a continued need to identify the determinants of TRAIL pathway sensitivity in ovarian tumors, and other cancers, in order to improve our ability to use the TRAIL pathway agonists that are in clinical development alone and in combination with chemotherapy.